Drug-Receptor Interaction of Peptidic HIV-1 Protease: The Hydrophobic Effect-I

Abstract

When a drug interacts with its receptor, the nonpolar substituent of drug and receptor proteins attract each other because they have opposite magnitude with respect to each other. X-rays structure studies reflected that the S2/S2’ pocket in HIV-1 protease enzyme are essentially hydrophobic. The residues that make up these pockets are Val-32, Ile-47, Ile-50, and Ile-84 in each monomeric polypeptidic unit of the protease enzyme. Δπdr and ΔSASAdr have been used to measure the extent of hydrophobic interaction between peptidic protease inhibitors and receptor proteins (binding site: valine‒isoleucine; and catalytic site: glycine‒aspartic acid‒threonine) on the HIV-1 protease enzyme. For measurement of hydrophobic interaction, the molecular modeling and geometry optimization of all the inhibitors and the receptor amino acids have been carried out with CAChe Pro software by opting semiempirical PM3 methods. Log P was calculated using the atom-typing scheme of Ghose and Crippen, while solvent accessible surface area by conductor likes screening model. πd, πr, SASASd and SASASr well describe the hydrophobicities of the substituents and play the effective role for site selectivity for interaction of the drug with the receptor. Comparative study of values of Δπdr and ΔSASAdr show the order of hydrophobic interaction with respect to amino acids: Asp > Thr > Val > Ile and Thr > Val > Asp > Ile, respectively. Further, comparative study of the values of (ΣΔπdr)binding-site, (ΣΔπdr)catalytic-site, (ΣΔSASAdr)binding-site, (ΣΔSASAdr)catalytic-site shows that peptidic HIV-1-PRIs interact with binding site rather than catalytic site as binding site have lower value of ΣΔπdr and ΣΔSASAdr. Among the binding site, Val has maximum interaction than Ile, as it has lower vale of Δπdr and ΔSASAdr.